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Drug Action 1
Physiology and Pharmacology
| Question | Answer |
|---|---|
| What is a drug | A chemical compound that when applied to a biological system alters its function in a specific manner |
| What is a drug target | Any biological binding/recognition element (usually protein) for drugs |
| Main types of drug targets | Receptors Ion channels Carriers or transporters Enzymes |
| Examples of drug targets | Tubulin - by paclitaxel for cancer Immunophilins - by cyclosporin as an immunosuppressant Cytokines - by therapeutic antibodies for IBD DNA - by alkylating agents for cancer Bacterial cell walls - by polymyxins as an antibiotic |
| Drugs with non-receptor mediated mechanisms | Antacids Laxatives (mechanical stimulation) Osmotic diuretics |
| Drug target interactions | Agonist and target binding (Occupation) determined by affinity Activation of this complex determined by efficacy Antagonist and target only has affinity - no efficacy as no response is produced |
| Affinity | Chemical forces involved in the association of a drug with its target |
| Efficacy | Ability of a drug to activate the target and produce a response |
| Types of receptors | Cellular macromolecules that recognise and respond to endogenous chemical signalling Classification takes into account molecular structure and type of transduction mechanism |
| 4 main types of receptor | Type 1 - ligand gated ion channels (inotropic receptors) Type 2 - G protein coupled receptors (metabotropic receptors) Type 3 - Kinase linked receptors Type 4 - Nuclear receptors |
| Roles of each receptor type | Type 1 - changes in membrane potential (rapid response) Type 2 - Protein phosphorylation, Ca release, change in excitability Type 3 - Protein and receptor phosphorylation, Guanylate cyclase activity Type 4 - control of gene expression (slowest) |
| Receptor subtypes | These exist in each group. Can differ in primary structure, so have different 3D shape, which affects sensitivity to drugs E.g. different subtypes of nicotinic Ach receptors found in brain and skeletal muscle |
| What causes receptor subtypes | Different genes Post-transcriptional modification, including mRNA splicing and editing |
| Alternative splicing | Removal of introns from pre-mRNA Exons can be put back in many different orders to give multiple different proteins from one gene. E.g. can give rise to GPCRs with different pharmacological properties |
| mRNA editing | Substitution of on base in the mRNA - C to U or A to I (inosine, which functions as guanine) This editing is random so gives rise to many subtypes in one cell E.g. editing of glutamate receptor subunit GluR-6 in the CNS |
| Type 1 - Ligand gated ion channels | 4 transmembrane domains, with a N-terminus binding domain and a channel pore. 4 or 5 join together to firm a channel -ve residues on the entrance/exit allow cations through, whilst +ve residues allow anions through Control fast responses in NS |
| Examples of Type 1 receptors | Nicotinic Acetylcholine receptor - 5 subunits - allows cations GABAa receptor - 5 subunits - allows Cl 5-HT3 receptor - 5 subunits - allows cations Glycine receptor - 5 subunits - allows Cl NMDA receptor - 4 subunits - allows cations |
| Type 2 - G protein coupled receptors | 7 transmembrane domains Binding domain on outside of cell for peptides and inside membrane for small molecules Allows g proteins to reach and activate other proteins Many neurotransmitters act on GPCRs Some activated by N-terminus cleavage |
| Mechanism of G protein activation | GDP bound to alpha subunit. Ligand binds to receptor, triggering a conformational change. Receptor has high affinity for G protein, so protein trimer binds GDP exchanged for GTP, releasing subunits to act on other proteins Hydrolysis of GTP terminates |
| Amplification of GPCR | Individual agonist-receptor complex activates multiple G proteins Active G protein can interact with effector enzymes for a duration sufficient to generate many products Second messengers allow for amplification |
| Targets of G proteins | Adenylyl cyclase - cAMP activation Phospholipase C - IP3 and DAG pathways Ion channels - modulated by by subunits Rho kinase - alpha subunit interacts with guanosine nucleotide exchange factor - activates rho kinase Mitogen-activated protein kinase |
| Types of GPCR | Gi - inhibitory effects when activated - uses adenylyl cyclase Gs - stimulatory effects when activated - uses adenylyl cyclase Gq - a GPCR which results in production of IP3 via phospholipase C |
| Example of GPCR pathway | Beta adrenergic receptors - adrenaline binds to Gs receptor, activating cAMP. Alpha subunit binds to adenylyl cyclase which converts ATP to cAMP. This activates PKA and initiated CA influx, leading to contraction. B blockers prevent the adrenaline binding |
| Type 3 - Kinase linked receptors | Single transmembrane domain with a binding and catalytic domain. This activates phosphorylation cascades. Examples include tyrosine kinases, serine/threonine kinases and cytokine receptors |
| Example of a Type 3 receptor - epidermal growth factor | GF binds to receptor, causing dimerization. The tyrosine's present auto phosphorylate, and bind SH2 protein, activating a kinase cascade pathway which leads to a change in gene expression Mutations in components of this are found in cancer |
| Type 4 - Nuclear receptors | Soluble, non-membrane bound receptors Contain 2 binding domains and a DNA binding domain made of zinc fingers. Control gene expression Class 1 - present in cytoplasm, used for steroids Class 2 - found in the nucleus, used for lipids |
| Channel proteins | Form aqueous pores in membranes Usually posses a gate Passive transport Ligand gated or voltage gated |
| Transporter proteins | Conformational changes required for transfer Passive or active transport Coupled transporters - uphill transport of one solute powered by downhill transport of another ATP driven pumps |
| Drugs affecting channels | Blockers - occlude permeation pathway directly e.g. local anaesthetics on Na channels Modulators or gating modifiers bind to areas on the protein and control the gate e.g. CFTR channel potentiators used in CF Indirect action e.g. gabapentin |
| Drugs affecting transporters | Inhibitors - prevent transport e.g. cocaine competitively inhibits monoamine transporters The multidrug resistance associated protein may transport anticancer drugs out cells, so blockers for these are needed |
| Drugs affecting enzymes | Inhibitors - prevent normal reaction e.g. aspirin inactivated COX False substrate - drug undergoes enzymatic processing to form an anormal product that interferes in a cell e.g. fluorouracil an antic cancer drug replaces uracil, preventing cell division |
| What is enzyme processing needed for | Converting drugs to an active form - oseltamivir, an anti-influenza prodrug is activated in vivo by carboxylesterase 1 to form active oseltamivir carboxylase May cause toxicity -leads to formation of reactive metabolite e.g paracetamol effect on liver |
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